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Sevoflurane may be associated with a high incidence of emergence agitation in preschool children. We tested the hypothesis that maintenance of anesthesia with propofol after sevoflurane induction would reduce the incidence of this excitatory behavior compared with continuing sevoflurane for maintenance. We conducted a randomized, single-blinded, two-period, cross-over study in 16 preschool age children undergoing repeated brief general anesthetics for eye examination. After sevoflurane induction, patients were randomly assigned to receive either sevoflurane or propofol anesthesia for maintenance. The alternative anesthetic was used for the maintenance of anesthesia on the second occasion. We compared the speed and quality of recovery characteristics of these anesthetics, as well as, overall parent satisfaction with anesthesia. Eight patients first received sevoflurane and the remaining eight patients first received propofol. Of the patients who received sevoflurane for the maintenance of anesthesia, 38% developed emergence agitation. In contrast, none developed emergence agitation when propofol was administered for maintenance of anesthesia. Despite emergence agitation, sevoflurane provided a shorter postanesthesia care unit stay than propofol. Parent satisfaction with anesthesia was greater with propofol than with sevoflurane.

Implications In this cross-over study, we observed the incidence of emergence agitation with sevoflurane (38%) was significantly greater than with propofol (0%) in premedicated, preschool-aged children undergoing minor noninvasive surgery.

Department of Anesthesiology, Teikyo University and Ichihara Hospital, Chiba, Japan

Sevoflurane has gained popularity as an anesthetic for children because it is less pungent and has lower solubility and greater hemodynamic stability than the other potent inhaled anesthetics (1). However, sevoflurane may be associated with a greater incidence of emergence agitation than halothane in preschool age patients (2,3). A rapid recovery from sevoflurane, in conjunction with psychological immaturity of these young patients has been postulated for this emergence event (2). The underlying mechanisms for this agitation have not been defined (4). Possible etiologic factors include genetic predisposition, age (younger versus older), type of procedure (painful or not), duration of anesthesia, and concurrent medications (2–7).

Propofol is an alternative anesthetic for short procedures and provides a smoother recovery with greater patient satisfaction than sevoflurane, if it is used for maintenance of anesthesia in adult patients (8). Preliminary studies comparing two different groups of patients who received either sevoflurane or propofol may not have been matched for some of the factors previously mentioned, especially individual predisposition to emergence agitation (8–10).

Therefore, we performed a randomized, single-blinded, two-period cross-over study to compare the recovery profiles of these anesthetics in children undergoing repeated brief general anesthesia for eye examination performed by the same surgeon. We hypothesized that maintenance of anesthesia with propofol after sevoflurane induction would reduce the incidence of emergence agitation compared with continuing sevoflurane for maintenance. Although the emergence agitation associated with sevoflurane does not appear to have long-term adverse effects, it is certainly troublesome to caregivers and parents. Therefore, we also examined these anesthetics vis-à-vis parent satisfaction with their child’s anesthetic (11).

Methods

After obtaining institutional review board approval and informed consent from parents, 18 consecutive eligible patients previously diagnosed with retinoblastoma were enrolled in this study. They were all ASA physical status I or II preschool children ages 1–5 yr. The disease required routine eye examination under anesthesia on a regular basis (1 mo to 6 mo, decided by the surgeon). All of the patients had previous surgeries using mainly inhaled anesthetics, either sevoflurane or halothane (median times 6, range 3–10). No patients received propofol-based anesthesia before. Patients were excluded from the study if they had a history of a neurological disorder or had undergone a series of radiation therapy requiring daily general anesthesia.

Subjects received 0.5 mg/kg of oral midazolam as premedication 30 min before the induction of general anesthesia. When the patient arrived in the operating room, baseline hemodynamic data were recorded after the placement of routine monitors. Anesthesia was induced with an inhaled 5% sevoflurane in 95% oxygen, and the trachea was intubated after the administration of 0.1 mg/kg vecuronium. For maintenance of anesthesia, subjects were randomly assigned to receive either sevoflurane 2% to 4% end-tidal concentration, or a 2-mg/kg bolus of propofol followed by a continuous infusion of 100–400 μg · kg−1 · min−1 propofol. The dose of sevoflurane or propofol was adjusted to maintain heart rate and blood pressure within 20% of the preinduction values. All patients were ventilated by using 96% to 100% oxygen. For the second anesthetic procedure performed several months later, the alternative anesthetic was used under the same protocol. Rectal acetaminophen (30 mg/kg) was administered to each child immediately after the induction of anesthesia. No opioids were given intraoperatively.

All subjects were inpatients and followed a standard nothing orally order (no solids after midnight and unlimited clear liquids up to 2 h before premedication). The patients received 15 mL/kg of IV lactated Ringer’s solution for the first hour, then 5% dextrose in 0.45% normal saline at a maintenance rate for the remainder of the study. At the completion of surgery, residual neuromuscular relaxation was reversed with 50 μg/kg neostigmine and 20 μg/kg atropine, the anesthetics were discontinued, the stomach was suctioned, and the trachea extubated when the gag reflex, facial grimace, and purposeful movement were present.

The patients were then transferred to the postanesthesia care unit (PACU). Patients were discharged from the PACU when they satisfied the following criteria: stable vital signs, patent airway without manipulation, oxygen saturation >95% on room air, and adequate control of pain. On the ward, children were allowed to take oral fluids on request by the patient or the parents.

The provider of the anesthesia recorded patient demographic data (age, weight, sex), as well as, duration of surgery (time from the start of eye examination to the completion of the procedure), the induction time (time from start of mask induction to tracheal intubation), and duration of maintenance of anesthesia (time from the completion of tracheal intubation to the discontinuation of anesthesia). A blinded, independent anesthesiologist evaluated the speed of recovery from the anesthetics by using the following variables: time from the end of surgery to tracheal extubation, spontaneous eye opening, first oral intake, and the duration of PACU stay.

The same “blinded” anesthesiologist also assessed the quality of recovery from anesthetics by recording the presence or absence of emergence agitation in the PACU (defined as inconsolable crying, combative behavior, or thrashing), duration of this behavior, the incidence of emesis in the first 24 h, and the need for additional medications for pain relief. The mothers of the subjects were interviewed the first postoperative morning and asked to rank their satisfaction with their child’s anesthetic by using a scale of 1 = unsatisfied to 5 = highly satisfied.

The times of surgery, anesthesia, or recovery profiles were first analyzed with normal probability plots to validate that the normality assumption was not rejected. These numeric data are reported as mean ± sd and were analyzed by using paired t-tests. The parent satisfaction score was expressed as median and range and was analyzed by using Wilcoxon’s signed rank test. The incidence of adverse events (agitation and emesis) was compared by using Fisher’s binomial exact test. Statistical significance was accepted for P < 0.05.

Results

Two patients dropped out because the second examination did not occur within 6 mo from the first surgery. This resulted in 16 patients completing this cross-over study. Patients were 7 boys and 9 girls, ages 26 ± 15 mo and weighing 14 ± 6 kg (mean ± sd, respectively). Eight patients first received sevoflurane, and the remaining eight patients first received propofol. The previous anesthetic experiences between the patients who had propofol anesthesia for the first part of the study and those who had sevoflurane were comparable (6.5 [3–10] vs 6.5 [4–10], median [range]). The times of anesthesia and surgery were similar for the two anesthetics (Table 1).

Table 2 summarizes the speed and the quality of recovery from anesthesia. Sevoflurane provided a slightly faster recovery as evidenced by the time to spontaneous eye opening and the duration of the PACU stay. However, the incidence of agitation was significantly greater after sevoflurane; 38% (6 of 16) of the patients who received sevoflurane for the maintenance of anesthesia developed emergence agitation, whereas none developed emergence agitation after propofol anesthesia for maintenance (P = 0.03). Of the six patients who developed emergence agitation, sevoflurane was administered for maintenance anesthesia on the first occasion in four patients and on the second occasion in the remaining two. Median duration of agitation was 8 min (range 4–12 min). The agitation did not cause any cardiopulmonary compromise and resolved without any pharmacological intervention.

Among the total of 32 anesthetics, two episodes of postoperative emesis were recorded, both of which occurred on the ward after sevoflurane anesthesia. No patient required additional medication for pain in the PACU or the ward. The overall anesthesia experience perceived by parents was more favorable for propofol than sevoflurane.

Discussion

This investigation demonstrates that in preschool children undergoing a minor procedure, the use of sevoflurane as a maintenance anesthetic causes a greater incidence of emergence agitation compared with propofol (38% vs 0%). The incidence reported here is similar to those previously reported in a similar setting although the lack of a valid assessment of emergence behavior pattern in children may make comparison of the studies by using a different agitation scoring system difficult (2,3,6,7). In this study, we defined emergence agitation as a combative, excited, and disoriented behavior that requires transient physical restraint. Trivial degrees of excitement in which the patient was not calm, but could be easily comforted were not considered agitation. Emergence agitation is potentially dangerous if it is severe because the patient may fall off the bed, injure himself/herself, or the IV line may be pulled out. Continuous and intense attention is mandatory for acute caregivers, and transient physical restraint may be required to prevent injury.

Our results showed statistically but clinically insignificant faster early recovery from sevoflurane than from propofol. This finding is consistent with those of previous studies (8). However, these data should be interpreted with caution because we cannot guarantee that the patients were at the same depth of anesthesia during maintenance with sevoflurane and propofol. Comparison between inhaled and IV anesthetics in this regard is extremely complicated. We simply used hemodynamic variables for this purpose to duplicate common clinical practice, although these variables are not reliable in predicting the depth of anesthesia. Furthermore, it is possible that the faster early recovery after sevoflurane may have contributed to the incidence of agitation (2,3). Rapid awakening in an unfamiliar environment in psychologically immature preschool-aged children may account for emergence agitation (2). However, propofol anesthesia provided a similar, although statistically slower, immediate recovery profile. Therefore, rapid awakening from anesthesia may not necessarily cause emergence agitation; this leaves the possibility that sevoflurane might be a causative anesthetic for this behavior by unknown mechanisms. However, whether sevoflurane is the only inhaled anesthetic causing emergence agitation remains unknown. It would be interesting to know whether desflurane, which has a low solubility similar to sevoflurane, is associated with a high incidence of emergence agitation.

Emergence agitation may be the consequence of other etiologies, including hypoxemia, pain, bladder distension, and nausea. In this study, none of the patients experienced any of these problems during their PACU stay. It is unlikely that pain occurred in the recovery period because the surgical procedure was noninvasive, adequate doses of acetaminophen were given in the operating room, and agitation resolved without the administration of analgesics. However, there may be a relationship between midazolam premedication and sevoflurane-associated emergence agitation, although midazolam has been reported to reduce incidence of agitation by 40% (3).

The sevoflurane-induced emergence agitation was self-limited and short-lived (median duration was 8 min), and, therefore, was not pharmacologically treated. Despite emergence agitation, PACU stay was shorter after sevoflurane than propofol. Agitation may be treated with sedatives but at the cost of prolonging PACU stay time.

Earlier emergence from sevoflurane anesthesia failed to gain parent satisfaction. Instead, a slower, but smoother postoperative course after propofol anesthesia was more appealing to parents. This is not surprising, because the parents did not know the duration of PACU stay of their child. In fact, the differences in parent satisfaction would have been greater had they been allowed in the PACU and seen their child agitated. We speculate that lower parent satisfaction with sevoflurane could be mostly because of poor behavior (e.g., bad mood, intermittent cry) of the children while they were on the floor with their parents, because five of six parents whose children experienced emergence agitation after sevoflurane anesthesia expressed a preference for the alternative anesthetic technique.

Our patients underwent a nonpainful procedure. Therefore, whether our results are applicable to more painful procedures is speculative, because pain may be a significant contributor to the occurrence of emergence agitation (4).

In conclusion, we have demonstrated that the use of sevoflurane for maintenance of anesthesia for minor noninvasive surgery in preschool-aged, premedicated children is associated with a greater incidence of emergence agitation, whereas propofol anesthesia after sevoflurane induction is not.